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Eur J Drug Metab Pharmacokinet DOI 10.1007/s13318-015-0296-z

Eur J Drug Metab Pharmacokinet DOI 10.1007/s13318-015-0296-z REVIEW Pharmacokinetic Herb-Drug Interactions: Insight into

REVIEW

REVIEW

Pharmacokinetic Herb-Drug Interactions:

Insight into Mechanisms and Consequences

Enoche F. Oga 1 Shuichi Sekine 2 Yoshihisa Shitara 3 Toshiharu Horie 4

Springer International Publishing Switzerland 2015

Abstract Herbal medicines are currently in high demand, and their popularity is steadily increasing. Because of their perceived effectiveness, fewer side effects and relatively low cost, they are being used for the management of numerous medical conditions. However, they are capable of affecting the pharmacokinetics and pharmacodynamics of coadministered conventional drugs. These interactions are particularly of clinically relevance when metabolizing enzymes and xenobiotic transporters, which are responsible for the fate of many drugs, are induced or inhibited, sometimes resulting in unexpected outcomes. This article discusses the general use of herbal medicines in the man- agement of several ailments, their concurrent use with conventional therapy, mechanisms underlying herb-drug interactions (HDIs) as well as the drawbacks of herbal remedy use. The authors also suggest means of surveillance and safety monitoring of herbal medicines. Contrary to popular belief that ‘‘herbal medicines are totally safe,’’ we are of the view that they are capable of causing significant toxic effects and altered pharmaceutical outcomes when coadministered with conventional medicines. Due to the paucity of information as well as sometimes conflicting reports on HDIs, much more research in this field is

& Enoche F. Oga eoga@uclan.ac.uk

1 School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire PR1 2HE, UK

2 Department of Biopharmaceutics, Chiba University, Chiba, Japan

3 Pharmacokinetics Laboratory, Meiji Seika Pharma Co., Ltd, Yokohama, Japan

4 Department of Biopharmaceutics and Molecular Toxicology, Teikyo Heisei University, Tokyo, Japan

needed. The authors further suggest the need to standardize and better regulate herbal medicines in order to ensure their safety and efficacy when used alone or in combination with conventional drugs.

Key Points

Herbal medicines are usually a complex mixture of chemical constituents whose bioactive components in many instances are yet to be fully characterized, but are believed to be medicinally efficacious

Metabolizing enzymes and xenobiotic transporters, which are responsible for fate of many drugs, could also be induced or inhibited by these herbal medicines

Clinically relevant herb-drug interactions may occur following their coadministration, sometimes resulting in fatal consequences, informing the need for caution in the use of these herbal medicines as well as more controlled clinical studies in order to fully clarify the underlying mechanisms for these altered drug effects

1 Overview of Herbal Medicine Use

Herbal medicine comprises the use of plant parts for medicinal purposes. Unlike conventional drugs, most her- bal medicines are a complex mixture of chemical con- stituents whose bioactive components in many instances are yet to be fully characterized, but have been reported to be medicinally efficacious [1]. There is a long history of

are yet to be fully characterized, but have been reported to be medicinally efficacious [ 1

E. F. Oga et al.

the use of these phytomedicines, with herbalism having a long tradition of use outside of conventional medicine. Their use has become more established as improvements in analysis and quality control as well as advances in clinical research have shown their value in treating and preventing disease [2]. In some developing countries, up to 80 % of the indigenous populace is known to depend on traditional systems of medicine and medicinal plants as their primary source of healthcare [3, 4]. This occurrence is not signifi- cantly different across the globe. For instance, reports show that over 70 % of German physicians prescribe herbal medicines and over 75 % of the German populace has used complementary or natural medicine [5]. In countries like the USA, an increase in their use has been reported because of dissatisfaction with the cost of prescription medications, combined with an interest in returning to natural or organic medicines [6]. In Japan, about 148 kinds of Japanese herbal medicines (Kampo medicines) have been approved and are listed on the National Health Insurance Drug Tariff. These medicines are reportedly prescribed by 72–78 % of Japa- nese physicians [7, 8]. These plant-based medicines are believed to be increasingly utilized because of their low cost, perceived safety, efficacy and lower incidence of adverse effects when compared to orthodox medicines. While their use is on the increase in some countries, stringent regulatory requirements in other countries make it difficult to register herbal medicines, therefore their reported limited use [9]. In the UK, herbal medicines have been recognized as substances that pose particular chal- lenges for public health, and effective regulation is being sought that would safeguard the public. To this end, there have been deliberations on the need for statutory regulation

of UK herbal medicine and its practitioners [10, 11]. It is worth noting that approximately 30–50 % of conventional medicines in use evolved from natural products from which they are synthesized as pharmaceutical preparations [1214]. For instance, the medicines Catharanthus roseus (vincristine), Atropa belladonna (atropine), Cinchona sp. (quinine), Cephaelis ipecacuanha (emetine), Digitalis purpurea (digitoxin and digoxin), Ephedra sinica (ephe- drine), (Artemisia annua (artemisinin), Rauwolfia serpen- tine (reserpine) and Podophyllum peltatum (etoposide) among several others. The main focus of this article is evidence for pharma- cokinetic herb-drug interactions. A review of the litera- ture reporting herbal medicines, their effects and documented interactions with conventional drugs was conducted between January 2012 and June 2015 on research databases. Relevant studies were identified through searches of electronic databases, citations, refer- ence lists, comprehensive pearl-growing and handsearch- ing-related journals, and conference proceedings. The relevant online databases (including PubMed, Cochrane database, Google Scholar and Web of Science) were uti- lized using online keyword searches, with searches limited by date to reports published from 1985 onwards.

2 Mechanisms of Herb-Drug Interactions

Similar to conventional pharmaceutical products, pharma- cokinetic and pharmacodynamic alterations are the two mechanistic pathways through which herb-drug interac- tions (HDIs) occur, resulting in null, beneficial or toxic

Fig. 1 Illustration of the main mechanisms of herb-drug interactions with some examples ( OATP organic anion transporting polypeptides, P-gp permeability glycoprotein)

Herb-Drug Interac ons

P-gp permeability glycoprotein) Herb-Drug Interac ons Pharmacodynamic Pharmacokine c • Addi ve •
P-gp permeability glycoprotein) Herb-Drug Interac ons Pharmacodynamic Pharmacokine c • Addi ve •
P-gp permeability glycoprotein) Herb-Drug Interac ons Pharmacodynamic Pharmacokine c • Addi ve •
P-gp permeability glycoprotein) Herb-Drug Interac ons Pharmacodynamic Pharmacokine c • Addi ve •

Pharmacodynamic

Pharmacokine c

Addi ve

Synergis c

Antagonis c

Eg.

Kava (Piper methys cum)+ Benzodiazepines

Guarana (Paullinia cupana)+ Seda ves

Comfrey (Symphytum officinale ) + Acetaminophen

Drug Transporters

Efflux (Eg. P-gp)

Uptake (Eg. OATP)

Metabolizing enzymes Phase I Phase II
Metabolizing enzymes
Phase I
Phase II

Changes in absorp on, distribu on, metabolism, excre on, protein binding leading to a change in the level of drug and/or metabolite(s)

Eg.

St John’s Wort + Ritonavir

Milk thistle + Warfarin

St John’s Wort + Indinavir

Eg. • St John’s Wort + Ritonavir • Milk thistle + Warfarin • St John’s Wort

Pharmacokinetic Herb-Drug Interactions

responses (Fig. 1). In addition to the cytochrome enzymes, membrane transporters are known to play an important role in the modulation of absorption, distribution, metabolism and excretion of drugs [15]. These HDIs arise from chan- ges in the function and expression of transporters or enzymes that mediate the absorption and elimination of drugs in the small intestine, kidney and liver [16].

2.1 Enzyme-Mediated HDIs

One of the most important causes of clinically relevant HDIs is the inhibition or induction of the activity of cytochrome P450 (CYP), a superfamily of enzymes cat- alyzing extremely diverse and often complex reactions in the metabolism of numerous drugs, phytomedicines and xenobiotics. CYPs are the main enzymes involved in drug metabolism, with the majority of drugs interacting with the CYP3A isoform [17, 18]. For instance, several intestinal CYP3A inhibitors (including the triterpenes, maslinic acid, corosolic acid and ursolic acid) have been isolated from Vaccinium macrocarpon (cranberry) [19]. Cranberry is now commonly taken as a treatment for urinary tract infections because of a group of proanthocyanidins that exhibit bacterial antiadhesion activity against both antibi- otic-susceptible and -resistant strains of uropathogenic Escherichia coli bacteria [19, 20]. Another study revealed that cranberry juice inhibits the CYP3A-mediated meta- bolism of nifedipine, altering its pharmacokinetics by increasing the concentration of nifedipine in rat plasma [21]. The study demonstrated that the oxidative activities of nifedipine in rat intestinal and human hepatic micro- somes were inhibited after preincubation with cranberry juice [21]. However, a clinical study in ten healthy vol- unteers involving the CYP3A probe substrate, midazolam and a cranberry juice product suggested that an interaction was unlikely [22]. Interestingly, in a more recent study that utilized a systematic approach, from in vitro assay (Caco-2 cell and human intestinal microsomes) to a clinical study in 16 healthy volunteers, it was observed that a cranberry juice product revealed a pharmacokinetic interaction with midazolam [23]. The difference in the finding of these studies suggests the importance of utilizing clinical regi- mens and taking into consideration the interbrand variation of natural products in the design of pharmacokinetic studies. Similarly, the widely used herbal remedy Echi- nacea purpurea (Echinacea) has been reported to signifi- cantly induce CYP3A [24]. It has been shown to selectively modulate the catalytic activity of CYP3A at hepatic and intestinal sites, suggesting that CYP3A substrates with relatively high bioavailability may be more susceptible to Echinacea -mediated interactions [25, 26]. As CYP3A is the main drug-metabolizing enzyme, the potential of HDIs occurring with Echinacea purpurea may be high.

2.2 Transporter-Mediated HDIs

Although most studies have focused on CYP-based drug interactions, the influence of transporters as a mechanism for HDIs is increasingly being documented, as it has been revealed that they can play an important role in modulating drug absorption, distribution, metabolism and elimination. Figure 2 illustrates the distribution of relevant transporters in the main organs responsible for drug disposition. Xenobiotic transporters are generally categorized into the ATP-binding cassette (ABC) and solute-carrier (SLC) superfamilies.

2.2.1 ATP-Binding Cassette-Based HDIs

ABC transporters function as barrier proteins extruding toxins and xenobiotics out of cells. They include p-glyco- protein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) as well as several multidrug- associated resistance proteins (MRPs). They are commonly expressed on barrier epithelia where they mediate transport across cell membranes [15]. These transporters are signif- icant determinants of the pharmacokinetics, efficacy and toxicity of xenobiotics (including phytomedicines), and coadministered drugs may inactivate, inhibit or induce these transporters. Of all the transporter-mediated HDIs, P-gp-based interactions are the most studied. There are reports on the modulation of P-gp by herbs such as Hypericum perforatum (St. John’s wort), Vernonia amyg- dalina (Bitter leaf), Tapinanthus sessilifolius (African mistletoe), Coptis chinensis (Chinese goldthread), Ginkgo biloba (Maidenhair tree), Piper nigrum (Black pepper) and Glycorrhiza glabra (Licorice) [16, 27, 28].

2.2.2 Solute Carrier-Based HDIs

The solute carrier (SLC) transporters mainly comprise uptake transporters including the organic anion transport- ing polypeptides (OATPs), organic cation transporters (OCTs), organic anion transporters (OATs), peptide transporters (PEPT) and multidrug and toxic compound extrusion transporters (MATEs) [15]. These SLC trans- porters are known to facilitate absorption of phytomedici- nes and xenobiotics into the systemic circulation. Because transporters are mainly expressed in the intestinal epithelial cells and organs of elimination (kidney proximal tubules and liver hepatocytes), they can significantly influence the disposition of herbal medicines [29]. Fewer reports inves- tigate the influence of SLC-mediated herb-drug interac- tions when compared to ABC transporters, where the majority of the studies examine the interaction with P-gp [30]. However, several interesting drug-food interactions with fruit juices involving uptake transporters have been

P-gp [ 30 ]. However, several interesting drug-food interactions with fruit juices involving uptake transporters have

E. F. Oga et al.

a Enterocytes Uptake OATP Efflux PEPT1 BCRP Efflux Uptake MRP2 P-gp
a Enterocytes
Uptake
OATP
Efflux
PEPT1
BCRP
Efflux
Uptake
MRP2
P-gp

MRP3

OCT

b Hepatocytes BCRP BSEP MATE1 MRP2 OAT2 P-gp Uptake OATP1B1 Bile OATP1B3 OATP2B1 Efflux MRP2
b Hepatocytes
BCRP
BSEP
MATE1
MRP2
OAT2
P-gp
Uptake
OATP1B1
Bile
OATP1B3
OATP2B1
Efflux
MRP2
OCT1
MRP4
Apical membrane Basolateral membrane c Renal tubular cell MATE1 OAT1 MATE2-K OAT2 MRP2 Efflux Uptake
Apical membrane
Basolateral membrane
c Renal tubular cell
MATE1
OAT1
MATE2-K
OAT2
MRP2
Efflux
Uptake
OAT3
MRP4
OATP4C1
OCTN1
OCT2
OCTN2
P-gp
Blood
Renal lumen

Fig. 2 Transporter expression in the main organs influencing drug disposition ( a ). Uptake and efflux transporters at the apical and basolateral membranes of enterocytes (b ). Uptake and efflux trans- porters in hepatic cells ( c ). Uptake and efflux transporters in the renal epithelial cells ( BCRP breast cancer resistance protein, BSEP bile salt

reported [31, 32]. For instance, grapefruit juice inhibition

of OATP resulted in reduced blood concentrations of fex-

ofenadine, celiprolol, talinolol and acebutolol [33]. On the

contrary, concurrent intake of grapefruit juice has been shown to increase the in vivo plasma concentrations of many drugs. This has been attributed to various factors, including, the inhibition of P-gp and an inhibition of

intestinal CYP3A4, resulting in an increase in the fraction of drug absorbed [34]. Other clinical reports on SLC transporters include a study in healthy volunteers on bai- calin from Radix scutellariae (Baikal skullcap), which showed a reduction in the plasma concentration of coad- ministered rosuvastatin as a result of OATP modulation [35]. In the study, the observed decrease in the plasma concentration of rosuvastatin in the presence of baicalin was thought to be partially mediated by baicalin’s induc- tion of hepatic rosuvastatin uptake through OATP1B1 [35].

A study in rats reported that the pharmacokinetic disposi-

tion of salvianolic acid B was altered by rifampicin because

of the inhibition of Oatp-mediated influx [36]. Salvianolic

acid B is one of the most bioactive components of Salvia

acid B is one of the most bioactive components of Salvia export pump, MATE multidrug and

export pump, MATE multidrug and toxic compound extrusion transporters, MRP multidrug-associated resistance proteins, OAT organic anion transporters, OATP organic anion transporting polypep- tides, OCT organic cation transporters, OCTN carnitine/organic cation transporter, P-gp permeability glycoprotein)

miltiorrhiza (Red sage), a traditional Chinese herbal med- icine that is commonly used for the prevention and treat- ment of cerebrovascular and cardiovascular disorders. Likewise, herbs modulating OAT1, a transporter actively involved in renal active secretion, have been reported [37]. Among several Chinese herbal medicines examined in the study, Gui Zhi Fu Ling Wan (commonly formulated as a mixture of Ramulus cinnamomi , Poria cocos , Cotex mou- tan , Radix paeonia and Semen persicae ) and Chia Wei Hsiao Yao San (commonly formulated as a mixture of Radix bupleuri , Radix glycyrrhizae , Angelica sinensis and Paeonia alba ) exhibited significant inhibitions on hOAT1- mediated [ 3 H]-p-amino hippuric acid uptake in vitro as well as p-amino hippuric acid clearance and net secre- tion in vivo [37].

2.3 Dual Enzyme- and Transporter-Mediated HDIs

Some phytomedicines are known to influence both trans- porter and CYP function. P-gp and CYP3A4 both consti- tute a highly efficient barrier for many orally absorbed

Pharmacokinetic Herb-Drug Interactions

drugs with a wide overlap in their substrates [38]. Rhodiola rosea (Golden root), a herbal medicine used in the man- agement of depression, has shown potent inhibition of both P-gp and CYP3A4 [39]. Also, St. John’s wort ( Hypericum perforatum), one of the most widely used herbal medicines, with several medicinal effects including its recognized antidepressant properties, induces both CYP3A and the efflux transporter, P-gp [40]. A recent study revealed that quercetin and rutin, which are common herbal flavonoids, induced the functions of both P-gp and CYP3A4 by decreasing the bioavailability of coadministered cyclos- porin [41]. These alterations of normal P-gp efflux and CYP activity have an impact on the pharmacokinetic dis- position of CYP3A and P-gp substrate drugs when coad- ministered, leading to changes including lower efficacy and/or the emergence of toxicity [42].

2.4 Influence on Transcriptional Regulators

Several CYPs and transporters that influence drug dispo- sition can be induced by xenobiotics and herbs [43]. The nuclear receptors pregnane X receptor (PXR) and consti- tutive androstane receptor (CAR), which are present in the small intestine and liver, have emerged as transcriptional regulators of CYPs (especially CYP3A, -2B6, -2C8, -2C9 and -2C19) and drug transporters: P-gp, MRP2 and OATP [44, 45]. Besides the various xenobiotics that have been reported to activate PXR, herbals including St. John’s Wort are known to potently induce it [46]. These nuclear receptors have also been reported to enhance the expres- sion of phase II-conjugating enzymes such as uridine 5 0 - diphospho-glucuronosyltransferase (UDP-glucuronosyl- transferase, UGT), sulfotransferase and glutathione- S - transferase enzymes [47, 48]. As a result of an increased induction of these nuclear receptors, there is an enhanced expression of P-gp and CYPs, which is likely to reduce the rate of absorption and increase the rate of elimination of drug substrates.

3 Herbal Medicine Use and Interactions with Conventional Drugs

Several evidence-based studies on clinically relevant HDIs have been documented. Table 1 summarizes some clini- cally significant herb-drug interactions.

3.1 Cancer

Because of the high global incidence of cancer, the use of herbal medicines by cancer patients is quite common with an increasing number of cancer patients making use of complementary and alternative medicines in combination

with their conventional chemotherapeutic treatment [49]. Among cancer patients in general, between 7 and 48 % have reported taking herbal medicines [50]. These herbal medicines are used by cancer patients with the belief that they are capable of killing tumor cells, improving cancer- related symptoms as well as reducing the adverse drug effects posed by the therapy [51]. However, in order to appropriately integrate herbal medicine use into conven- tional cancer therapy, pharmacological and clinical studies must be carried out on these herbals, with relevant moni- toring for the emergence of adverse effects [52]. This is of particular importance as several chemotherapeutic agents are known to have considerable interindividual pharma- cokinetic variability, which coupled with their narrow therapeutic index may pose a higher risk for the occurrence of toxic HDIs. For instance, St. John’s wort has been reported to induce the metabolism of imatinib, an oncolytic used in the management of chronic myelogenous leukemia and gastrointestinal stromal tumors. These studies showed an alteration in the pharmacokinetics of imatinib when coadministered with St. John’s wort due to an induction of CYP3A [53, 54]. This induction of CYP isoenzymes and drug transporters would often lead to therapeutic failure as a result of a lower plasma concentration of the anticancer drugs [49]. Likewise, a pharmacodynamic interaction involving irinotecan (a potent anticancer drug for the management of advanced colon cancer), which may cause severe diarrhea as an adverse effect, has been reported to have worsened diarrhea on coadministration of St. John’s wort through downregulation of intestinal proinflammatory cytokines and inhibition of intestinal epithelial apoptosis [55]. In another study, the metabolism and toxicity of irinotecan was altered on coadministration with St. John’s wort with a compromise in overall antitumor activity [56]. Grapefruit juice intake has been reported to alter the pharmacokinetics of the cytotoxic drug, etoposide, with a clinical study revealing a 26.2 % decrease in the area under the plasma concentration-time curve (AUC) of etoposide after oral administration. It was postulated that the alter- ation of intestinal P-gp-mediated transport was a possible explanation for the observed effect [57]. Several in vitro studies have been reported with pointers to the possibility of relevant herb-drug interactions. For example, Gin- senoside Rh2 from Panax ginseng significantly enhanced the cytotoxicity of daunomycin and vinblastine in adri- amycin-resistant P388 leukaemia cells [58]. Another pharmacologically active constituent from Panax ginseng, Ginsenoside Rg3, inhibited the efflux of vinblastine and reversed resistance to doxorubicin and vincristine in drug- resistant KBV20C cells [59]. Competition of Ginsenoside Rg3 for binding to P-gp was demonstrated as the mecha- nism for the inhibition of drug efflux. The study showed that ginsenoside Rg3 was an effective modulator in

as the mecha- nism for the inhibition of drug efflux. The study showed that ginsenoside Rg3

E. F. Oga et al.

References

[49, 53,

[49, 55,

[134]

[133]

[102]

[128]

[131]

[135]

[130]

[134]

[136]

[132]

[129]

[126]

[127]

54]

56]

[98]

[71]

[68]

Median number of leucocytes : significantly in comparison to the control group

Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with ; oral fexofenadine C p

10 days of treatment with St. John’s wort ; digoxin AUC (024) by 25 %

One case reporting a possible interaction between etoposide, and echinacea which resulted in trombocytopenia requiring a platelet transfusion

Long-term dose significantly ; C max of fexofenadine by 35 % and

Significant reduction of stool weight and stool frequency in AIDS

Orange juice ; the AUC, C max and the urinary excretion values fexofenadine

Goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity

Single dose significantly : C max of fexofenadine by 45 % and

The consumption of curcumin ; AUC and C max of talinolol

in the mean C max of indinavir from 12.3 to 8.9 l g/mL

: blood pressure when combined with thiazide diuretics

42 % ; in C p of the active metabolite of irinotecan

AUC 08 of indinavir decreased by a mean of 57 %

Significantly decreases the systemic exposure and

49–99 % ; in concentration 8 h post-dosing

52 % ; in AUC and 28 % ; in C a max

significantly ; oral CL by 20 % b

significantly : oral CL by 47 % c

: in CL of nevirapine by 35 % a

mean saquinavir AUC by 51 %

: C max of nifedipine by 29 %

Significant ; in C max and t 1/2

of up to 32 % mean AUC

patients who had diarrhea

Effect in human subjects

43 % : in imatinib CL

: hypoglycaemia

C max by 54 %

;

;

;

Goldenseal (Hydrastis canadensis )

Grape fruit juice ( Citrus paradisi )

Echinacea (Echinacea purpurea )

Orange juice ( Citrus sinensis )

SP-303 (an extract of Croton

Curcumin ( Curcuma longa )

St. John’s wort ( Hypericum perforatum )

Ginseng ( Panax ginseng )

Gingko ( Gingko biloba )

Garlic ( Allium sativum )

Herbal medicine

St. John’s wort

St. John’s wort

St. John’s wort

St. John’s wort

St. John’s wort

St. John’s wort

Echinacea

lechler )

Garlic

Table 1 Clinically relevant herb-drug interactions

Conventional drug

Protease inhibitors

Chlorpropamide

5-Fluoro uracil

Fexofenadine

Fexofenadine

Fexofenadine

Debrisoquin

Simvastatin

Nevirapine

Leucovirin

Saquinavir

Nifedipine

Irinotecan

Etoposide

Etoposide

Thiazides

Indinavir

Talinolol

Imatinib

Digoxin

Cardiovascular disease

Asthma and allergy

HIV/AIDS

Disorder

Diabetes

Cancer

Thiazides Indinavir Talinolol Imatinib Digoxin Cardiovascular disease Asthma and allergy HIV/AIDS Disorder Diabetes Cancer

Pharmacokinetic Herb-Drug Interactions

from time zero to time t , CL clearance, C max maximum plasma concentration, C p

References

[138140]

[144]

[145]

[147]

[143]

[146]

[147]

[137]

[142]

[148]

[132]

[137]

[141]

[131]

[105]

[25]

[42]

[25]

increased significantly with grapefruit and

Significant : in oral CL of norethindrone, : risk of unintended pregnancy and breakthrough bleeding

Significant ; in plasma concentrations of omeprazole and omeprazole sulphone

Significant ; in the half-life of ethinyl estradiol, : risk of unintended pregnancy

Increased serotonergic effects with risk of increased incidence of adverse

Garlic : clotting time and international normalized ratio (INR) of warfarin

Increased serotonergic effects with risk of increased incidence of adverse

Ginseng significantly ; warfarin’s anticoagulant effect by ; the INR and

Significantly : oral availability of midazolam after echinacea dosing

Potently inhibits platelet activating factor-mediated platelet aggregation

Echinacea dosing significantly ; the oral CL of caffeine

Green and black tea extracts ; folic acid bioavailability

Significantly : systemic CL of midazolam by 34 %

46 % ; in AUC and 42 % ; in C a,c max of cyclosporine

Goldenseal strongly inhibited CYP3A4/5 activity

Inhibition of iron absorption in young women

Significantly ; midazolam AUC by 23 %

Significantly ; alprazolam AUC by 54 %

and significant : of 5-hydroxyomeprazole

reducing plasma warfarin concentrations

; in AUC by 58 % a,c of cyclosporine

dextromethorphan

; anticoagulant effect of warfarin

and breakthrough bleeding

Effect in human subjects

a,d

: the fluidity of blood

seville orange of juice

inhibitor

Bioavailability

reactions

serotonin reuptake curve

reactions

selective concentration-time

Green tea ( Camellia sinensis )

Grapefruit (Citrus paradisi )

Chilli ( Capsicum annuum )

Bitter orange (Citrus aurantium )

the plasma

Herbal medicine

St. John’s wort

St. John’s wort

St. John’s wort

St. John’s wort

St. John’s wort

St. John’s wort

St. John’s wort

Goldenseal

Echinacea

Echinacea

under SSRI

Ginseng

Gingko

Ginkgo

Garlic

area life,

t 1/2 half

AUC (0t)

Triptans (sumatriptan, naratriptan, rizatriptan, zolmitriptan)

SSRIs (Citalopram, fluoxetine,

curve, ratio,

fluvoxamine, paroxetine, sertraline)

intestinal p-gp

3A4 p-gp

normalized

Conventional drug

intestinal

concentration-time

Dextromethorphan

Ethinyl estradiol

of CYP

of p-gp

Alprazolam

Midazolam

Midazolam

Norethindrone

Cyclosporine

INR international

Omeprazole

Tacrolimus

inhibition of

inhibition of

Folic acid

Ibuprofen

Warfarin

Warfarin

Warfarin

Warfarin

Caffeine

mechanism, induction

mechanism, induction

Iron

under the plasma

Vitamin supplementation

Mineral supplementation

Suggested mechanism,

Suggested mechanism,

Deep vein thrombosis

concentration,

Immunosuppression

Table 1 continued

Oral Contraception

CNS stimulation

Gastric ulcers

a Suggested

c Suggested

Antitussive

Depression

Headaches

AUC area

Disorder

plasma

d

b

a S u g g e s t e d c S u g g e

E. F. Oga et al.

restoring the sensitivity of resistant cells to doxorubicin, vincristine, etoposide and colchicine in human P-gp MDR cells at concentrations of 5–40 l M [59]. Although no clinical report on drug interaction studies involving gin- seng and P-gp substrates are known, these in vitro studies on its P-gp blockade role may point to its beneficial function as a natural multidrug resistance reversal agent

[60].

Also on a positive note, because of the hepatotoxicity caused by some conventional anticancer drugs, herbal medicines including Punica granatum (pomegranate), Phyllanthus emblica (Indian gooseberry), Mangifera indica (mango), Acacia catechu (Black cutch) and Camellia sinensis (Tea) have been used for their hepatoprotective and antioxidant properties when hepatotoxic chemotherapeutic agents are utilized [61]. Other herbal medicines used fre- quently by cancer patients include Zingiber officinale (gin- ger), Ginkgo biloba (ginkgo), Piper methysticum (kava- kava), quercetin (from several plants and also honey), Panax sp (ginseng), Curcuma longa (curcumin), Viscum album (European mistletoe), beta-carotene (especially from Dau- cus carota), Glycyrrhiza glabra (licorice), Astragalus membranaceus (astragalus), Viscum album (mistletoe), Echinacea sp. (echinacea), Berberis aristata (Indian bar- berry) and Allium sativum (garlic). These medications are perceived to be nontoxic, alleviate the symptoms of cancer, boost the immune system, manage the adverse effects of chemotherapeutics or even tackle the cancer itself [27, 62]. However, there is limited scientific evidence for their interaction with conventional drugs. On the whole, further research is required to prevent therapeutic failure and toxi- city in cancer patients when herbal medicines are concur- rently taken with conventional medicines. This would aid in establishing guidelines for their concomitant use.

3.2 HIV/AIDS

Around the world, the HIV epidemic rages on, emerging as the greatest challenge to global health. However, AIDS- related deaths are decreasing largely because of increased access to treatment. Herbal medicines are widely used by HIV patients to complement conventional therapy, with an increasing number of studies investigating their use in HIV management [63]. Common herbal medicines used during HIV management include Allium sativum (garlic), Euca- lyptus globulus (Blue gum) , Aloe vera, Trigonostema xyphophylloides , Vatica astrotricha , Vernonia amygdalina (Bitterleaf) , Lippia javanica (Fever tree) , Bidens pilosa (Blackjack) , Peltoforum africanum (Weeping wattle) , Hypoxis hemerocallidea (African star grass) and Moringa oleifera (Drumstick tree) [16, 64, 65]. However, it is of importance to thoroughly investigate the potential alter- ations in pharmacokinetic and toxicological profiles when

ations in pharmacokinetic and toxicological profiles when they are coadministered with conventional medicines as their

they are coadministered with conventional medicines as their concurrent use has resulted in beneficial and/or detrimental effects. For instance, an in vitro study revealed that Sutherlandia frutescens (Cancer bush) inhibited the metabolism of atazanavir in human liver microsomes and may have important implications for the absorption and metabolism and the overall oral bioavailability of ataza- navir [66]. Also the HIV protease inhibitor ritonavir on coadministration with some herbal components has been shown to modulate both P-gp and CYP3A4. In particular, the herbal constituents kaempferol and quercetin (from several plants), hypericin (from Hypericum perforatum) and allicin (from Allium sativum ) have been shown to inhibit the in vitro efflux and CYP3A4-mediated metabo- lism of xenobiotics and may interact with HIV antiretro- virals that are P-gp or CYP3A4 substrates, such as ritonavir [67]. Also, a clinical study in healthy volunteers demon- strated that St. John’s wort potently altered the pharma- cokinetics of indinavir (a protease inhibitor and known CYP substrate) via induction of CYP3A by St. John’s wort. As illustrated in Fig. 3, the study revealed a large reduction in indinavir concentrations by concomitant St. John’s wort. This finding has important clinical implications for HIV- infected patients receiving the two agents since low plasma concentrations of protease inhibitors are a cause of antiretroviral resistance and treatment failure [68]. Garlic is another herbal remedy commonly utilized by HIV/AIDS patients. Although some studies have shown that garlic has the potential to induce CYP isoenzymes, consequently reducing the effectiveness of antiretroviral drugs, in vitro assessments of its effect on CYPs are conflicting [69, 70].

of its effect on CYPs are conflicting [ 69 , 70 ]. Fig. 3 Mean concentration-time

Fig. 3 Mean concentration-time profile of indinavir alone (solid line) and with concomitant St. John’s wort ( dotted line ), showing a large reduction in indinavir concentrations by concomitant St. John’s wort. In the study, fasting participants received indinavir 800 mg orally. They then received two more doses at 8-h intervals to achieve steady- state. On the morning of day 2, an 800 mg dose was given. On day 3, participants began treatment with St. John’s wort (300 mg three times daily) for 14 days. Piscitelli et al. [68]. (Reproduced with permission from Elsevier)

Pharmacokinetic Herb-Drug Interactions

In a clinical study, garlic was shown to reduce the plasma pharmacokinetic concentrations of saquinavir by altering the CYP3A4 isoform of the CYP system, the isozyme through which saquinavir is metabolized, recommending patient caution on concomitant administration [71]. Another study in healthy volunteers examining the effect of an odorless garlic product indicated an insignificant reduction in the AUC and plasma concentrations of riton- avir following short-term garlic consumption [72]. This is thought to arise from transitory induction followed by inhibition on the various drug disposition pathways of ritonavir, especially as the treatment duration of garlic (twice daily for 4 days) was too short to observe a signif- icant change in ritonavir plasma concentrations [72]. This informs the need for caution, especially if large quanti- ties of raw or processed garlic are concomitantly taken with any protease inhibitor. Another study in healthy human subjects indicated a significant increase in the bioavailability and maximum plasma concentration of nevirapine following 6 days of piperine intake [73]. Piperine is a major component of Piper nigrum and Piper longum (black pepper and long pepper, respectively) and has been reported to inhibit drug-metabolizing enzymes and increase the plasma concentrations of several drugs,

are known to exhibit an antimalarial effect, antagonistic antimalarial properties when used in combination with artesunic acid in Plasmodium berghei-infected mice have been reported [78]. In the study, the extracts of Carica papaya when solely administered had good antimalarial activity. In a similar study, the influence of Eurycoma longifolia extract (commonly known as Tongkat ali, a herbal remedy commonly used in malaria therapy) was investigated on coadministration with artemisinin (WHO’s recommended first-line antimalarial) in experimental mice. Findings from that study revealed the suppression of par- asitemia in Plasmodium yoelii -infected mice. This is sug- gestive of a promising, potential antimalarial candidate by both oral and subcutaneous routes [79]. Similar synergistic herb-drug interactions involving goniothalamin ( Gonio- thalamus scortechinii) -chloroquine, Vernonia amyg- dalina —chloroquine and curcumin (isolated from Curcuma longa )-artemisinin combinations have been doc- umented with the suggestion that they be considered for future trials in the search for malaria combination therapy [8082]. Also, herbs can be combined for their additive effect as shown by the mixture of a Khaya ivorensis (African mahogany)- Alstonia boonei (English alstonia) extract mixture as an antimalarial prophylactic remedy

including P-gp substrates [74].

[83].

3.3 Malaria

3.4 Liver Diseases

Malaria is an important global public health issue with high morbidity and mortality rates. The majority of malarial endemic regions are from the world’s developing econo- mies. As a result of the relatively high costs for conven- tional antimalarials, many patients are known to take herbal medicines for its prevention and treatment [75]. Herbal medicines commonly used in the management of malaria include Vernonia amygdalina (Bitterleaf) , Piper longum (Long pepper) , Tapinanthus sessilifolius (African mistletoe), leaves of Carica papaya (Pawpaw), leaves and bark of Azadiractha indica (Neem) and rhizomes of Cur- cuma longa (turmeric) [76]. Sometimes these herbs are used alone or in combination with orthodox medicines. A study based on an in vitro (Caco-2 cell), ex vivo (Ussing chamber) and in vivo rat model revealed that extracts of Vernonia amygdalina, Tapinanthus sessilifolius and Carica papaya , which are herbals commonly used in traditional malaria, cancer and diabetes therapy, inhibited P-gp mediated digoxin transport [28, 77]. Findings from that study suggested that caution should be observed when those herbs are concomitantly used with P-gp substrate drugs as they may enhance their absorptive transport [28]. Frequently, antagonistic effects have been reported on coadministration of herbals and orthodox medicines. For instance, although the leaves of Carica papaya (Pawpaw)

Hepatic disorders (including alcoholic liver disease, hep- atitis, cirrhosis and steatosis) are still a cause for global concern [84]. Unfortunately, several orthodox drugs use- d in the management of liver diseases are inade- quate and sometimes can have serious side effects. However, herbal medicines have been used in the treat- ment of liver diseases since ancient times. Silybum mari- anum (milk thistle) is a widely used herbal remedy especially for the management of liver and gallbladder disorders [85]. Although preclinical evidence strongly supports its use as a hepatoprotectant, further well-de- signed clinical trials may be necessary to confirm this [86]. In-depth research has been conducted on its most active component, silymarin, a flavonoid complex. Silymarin and its active constituent, silybin, are believed to act as antioxidants, scavenging free radicals and inhibiting lipid peroxidation, thus finding use in chronic liver disorders [87, 88]. It is believed to be safe and well tolerated, with very minor side effects reported when taken within the recommended dose range (gastrointestinal upset, mild laxative effect and rare allergic reaction). Because of its vast use, significant work has been carried out, examining the potential for herb-drug interactions. In a study by Gurley et al. [89], insignificant changes in the disposition of digoxin were observed on coadministration with

study by Gurley et al. [ 89 ], insignificant changes in the disposition of digoxin were

E. F. Oga et al.

silymarin, posing no clinically significant risk for P-gp- mediated herb-drug interactions. On the other hand, a study has shown that silybin A and silybin B at clinically relevant concentrations inhibit CYP2C9-mediated metabolism of warfarin [90]. This HDI needs to be further evaluated because of the narrow therapeutic index of warfarin. In addition, there are several reports on the hepatoprotective function of glycyrrhizin (a major constituent of licorice). Besides inhibiting liver cell injury caused by many chem- icals, it is also used in the treatment of chronic hepatitis and cirrhosis [91]. Glycyrrhizin has been shown to be a strong inhibitor of 11- b -hydroxysteroid dehydrogenase (the enzyme responsible for catalyzing the conversion of cor- tisol to the inactive steroid cortisone) and is thought to alter the pharmacokinetics of prednisolone by inhibiting its metabolism. In one study, oral glycyrrhizin increased the plasma prednisolone concentrations in six healthy males

[92].

3.5 Asthma and Allergic Diseases

There are several reports on the use of herbal medicines in the treatment and management of asthma and allergic diseases (including allergic rhinitis, food allergy and atopic dermatitis), which affect a high percentage of the popula- tion. Some of these phytomedicines are used alone, while some others are used in combination with conventional medicines. Corticosteroids are known to form a key com- ponent in the management of asthma and allergy. A study investigated the interaction potential of cortisol on con- comitant administration with Glycyrrhiza glabra (licorice) and grapefruit juice. The findings showed significantly increased cortisol AUC and mean serum concentrations following the intake of licorice and grapefruit juice. Coadministration with grapefruit juice gave rise to a more complete intestinal absorption of cortisol during the first hours, indicative that interactions between various con- stituents and P-gp in the intestinal walls are implicated [93]. One study examined the relationship between the use of herbal medicines and adherence to inhaled corticos- teroids. It was revealed that utilizing herbal medicines was associated with lower adherence to inhaled corticosteroids and poor outcomes among asthmatic patients, probably because of patients’ worry over the adverse effects of the corticosteroids [94]. Petasites hybridus (Butterbur), a herbal remedy with antihistamine and anti-leukotriene activity, conferred complementary antiinflammatory activity in asthmatic patients who were receiving inhaled corticosteroids, suggesting the potential benefit in asthma management [95]. Although theophylline is commonly utilized in asthma therapy, its use complicated by its interaction with several other drugs and its narrow thera- peutic index. For instance, in a study its concomitant

peutic index. For instance, in a study its concomitant administration with St. John’s wort has resulted

administration with St. John’s wort has resulted in reduced plasma concentration of theophylline [96]. However, in another clinical study in healthy Japanese male volunteers, no significant alteration in the plasma pharmacokinetics of theophylline was observed when coadministered with St. John’s wort [97]. Likewise there are reports on herb-drug interactions involving fexofenadine, a well-known P-gp substrate probe that is commonly used in the management of allergy. A clinical study in healthy volunteers indicated a significant increase in the maximum plasma concentra- tion of fexofenadine and a significant decrease in its oral clearance following the administration of a single dose of St. John’s wort. In this study, no change in the half-life or renal clearance was observed [98]. This observation was also confirmed by another clinical study in healthy volun- teers that demonstrated that pretreatment with St. John’s wort significantly enhanced the oral clearance of fexofe- nadine by 1.6-fold. Here also no alteration in the half-life was observed. The authors suggested the predominant inductive effect of St. John’s wort on P-gp in the intestinal epithelium, which consequently caused a decrease in the absorbed fraction of oral fexofenadine [99]. As inhibition and induction of P-gp may significantly influence drug disposition, caution may need to be exercised in cases of their coadministration.

3.6 Depression

Several herbs have been used in the management of depression. Of particular note is Hypericum perfora- tum (St. John’s wort), which has gained widespread pop- ularity as ‘‘nature’s Prozac.’’ It has been used for centuries as a natural remedy for the treatment of a number of dis- eases [100]. Some clinical studies have provided evidence that it is as effective as conventional antidepressants. Although the antidepressive mechanism is not fully understood, its therapeutic effects have been confirmed in several studies when compared with placebo or standard antidepressant agents [101]. Even though it is widely obtained as an over-the-counter remedy, knowledge about the pharmacokinetics of ingredients and drug interactions of St. John’s wort is not commensurate. Because of its ability to induce CYP3A4/P-gp, there are some reports on its interaction with other CYP3A/P-gp substrates leading to pharmacokinetic interaction with drugs known to have narrow therapeutic windows (e.g. Digoxin), for which therapeutic drug monitoring may be necessary [102]. Because several drugs are cosubstrates of CYP3A and P-gp, their disposition is markedly affected by concomitant administration of St. John’s wort through an activation of nuclear receptors, resulting in enhanced metabolism and efflux transport of the coadministered substrate drug to different extents depending on the relative contributions of

Pharmacokinetic Herb-Drug Interactions

CYP3A and P-gp. For instance a study reported that the extent of induction measured by oral clearance was dif- ferent with CYP3A activity (midazolam, which is solely metabolized by CYP3A), which showed more increase than P-gp function (fexofenadine, a nonmetabolized drug), whereas with cyclosporine (CYP3A and P-gp are both

importantly involved in its disposition), the change in oral clearance appeared to be more closely associated with the increase in MDR1 than with CYP3A [99]. In general, most

of these studies support the need for caution as well as

stricter regulations of herbal medicines for safer drug therapy in medicine [103]. Panax ginseng is a widely used

herbal medicine, notably used for its antidepressant effect.

A study investigated the influence of Panax ginseng on

CYP3A function using the probe midazolam as a substrate probe [104]. Comparison of pharmacokinetic parameter values of midazolam was calculated and compared before and following the administration of Panax ginseng . As illustrated in Fig. 4, the findings revealed a significant reduction for the midazolam area under the concentration- time curve from zero to infinity, half-life and maximum concentration [104]. Also, American ginseng ( Panax quinquefolius ) reportedly reduces the effect of warfarin in healthy patients. This was observed in a clinical study in healthy volunteers following ginseng consumption for 2 weeks in which changes in the international normalized ratio, peak plasma warfarin concentration and warfarin AUC were found to be statistically significantly greater in the group [105]. Here, the effect was postulated to be as a result of the inductive effect of ginseng on the hepatic drug metabolizing enzyme system, as warfarin is known to be metabolized by the CYP system. Green tea (from Camelia

be metabolized by the CYP system. Green tea (from Camelia Fig. 4 Concentration-time profiles for midazolam

Fig. 4 Concentration-time profiles for midazolam ( ±SEM) before and after Panax ginseng administration. In this study, the participants were administered a single 8-mg oral dose of midazolam syrup. They then began taking P. ginseng at a dose of 500 mg twice daily for 28 days. On day 28 of P. ginseng administration, participants returned to the clinic for a repeat dose of midazolam. Malati et al. [104]. (Reproduced with permission from John Wiley & Sons, Inc)

sinesis ) is a popular beverage and dietary supplement with some reported interactions with conventional medicines. A study in healthy subjects examined its interaction potential with buspirone (a CYP3A4 substrate). The extract con- taining 800 g epigallocatechin gallate was administered daily for 4 weeks and was shown to significantly increase the bioavailability of buspirone [106]. Of note, however, is the fact that this CYP isozyme inhibition is unlikely to be of clinical relevance [106]. Another human study further revealed that a decaffeinated extract of green tea did not alter the pharmacokinetics of either dextromethorphan or alprazolam, indicating the improbability of green tea to alter the disposition of CYP2D6 or CYP3A4 substrates

[107].

3.7 Other Conditions

Herbal medicines are also widely used in the management colds, infections and inflammation. For instance, echinacea is commonly used for the treatment of the common cold, coughs, bronchitis, influenza, and inflammation of the mouth and pharynx, and it is one of the most sold herbal medicines in use, reportedly consumed by 10–20 % of herbal users [25]. Because of its immunostimulatory effect, it is also commonly used for HIV and upper respiratory tract infec- tions [108, 109]. In a study investigating the influence of Echinacea purpurea on the in vivo activity of CYP iso- zymes (including CYP3A4), after oral and intravenous midazolam administration, modulation of the catalytic activity of CYP3A4 at both hepatic and intestinal sites were reported. Inhibition of intestinal CYP3A4 activity was observed, with a potent increase in midazolam’s oral bioavailability as well as significant enhancement of mida- zolam’s systemic clearance by inducing hepatic CYP3A. In addition, the study advises the exercise of caution when it is coadministered with drugs that are dependent on CYP3A or CYP1A2 for their elimination [25]. Similarly, studies investigating interactions of Ginkgo biloba (Maidenhair tree) —a herbal remedy commonly used for memory enhancement—have been reported. For instance, a human study revealed a significant increase in the bioavailability and peak plasma concentration of tali- nolol as a result of P-gp efflux inhibition following long- term administration of ginkgo [110, 111]. This effect was suggested to be as a result of the P-gp inhibitory effect of some ginkgo flavonol constituents, including quercetin, kaempferol and isorhamnetin, which have been docu- mented [112]. In another study, the effect of the extract of Ginkgo biloba on midazolam (CYP3A4 substrate) and tolbutamide (CYP2C9 substrate) was investigated [113]. There, the AUC of tolbutamide following ginkgo intake was significantly reduced. Conversely, the AUC of mida- zolam was significantly enhanced, while its oral clearance

was significantly reduced. Conversely, the AUC of mida- zolam was significantly enhanced, while its oral clearance

E. F. Oga et al.

was decreased. However, another study reported the intestinal induction of CYP3A4 following midazolam administration to healthy humans. After administration for 4 weeks, the bioavailability and maximum plasma con- centration of midazolam significantly reduced with no change in the half-life suggestive of intestinal, but not hepatic, induction [113]. Another clinical study investi- gated the intake of the same dose of Ginkgo biloba extract after 2-week administration in combination with lopinavir, fexofenadine and midazolam [114]. The CYP3A4 induc- tive effect of ginkgo was indicated by a significant decrease in the AUC and maximum plasma concentration of mida- zolam. However, neither lopinavir nor ritonavir pharma- cokinetic parameter values were significantly altered. This is likely due to ritonavir’s more potent inhibition of CYP3A4. It was therefore suggested that Ginkgo biloba extract may unlikely reduce the exposure of ritonavir- boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected [114].

4 Drawbacks, Surveillance and Safety Monitoring of Herbal Medicines

Despite the fact that herbal medicines are widely used, the safety and efficacy profile of several of them are in doubt and unproven. Moreover, many consumers misinterpret the natural origin of herbal medicines as a sign of safety, without appreciating that herbal ingredients can cause serious adverse effects [115]. A major concern regarding the use of herbal medicines is their safety and toxicity profile. They may pose harm to patients under different circumstances through idiosyncratic or allergic reactions or the risk of herb-drug interaction occurring when taken concomitantly with conventional medicine. Because rig- orous testing and regulatory agency approval are not rou- tinely considered for many herbal medicines, they may be prone to easy adulteration or contamination, and thus harmful. Worldwide, several instances of toxicity have been reported on using herbal medicines. Of significance is the development of kidney failure by several women in Belgium after taking slimming pills containing the herb Aristolochic fangchi. This further resulted in transi- tional cell carcinoma in some of these patients [116]. In addition, standardization of herbal medicines sometimes becomes challenging as their chemical makeup differs depending on the part of the plant used, growing condi- tions, periods of harvest as well as storage conditions. Combination products composed of multiple natural products complicate matters further. In using herbal medicines, standardization, regulation and the scientific proof of patients’ safety are of paramount importance, especially in the development phase [117]. However, this is

in the development phase [ 117 ]. However, this is not the case in many instances

not the case in many instances and has resulted in the emergence of toxic responses. Although the use of herbal products is rapidly increasing, there are only few national surveillance systems monitoring and evaluating adverse reactions associated with their use [118]. In order to identify and assess the possible risks associated with herbal medicine use, pharmacovigilance studies are essential. For this, the establishment of phar- macovigilance centers would play a significant role in pro- moting awareness of herbal medicine safety and the need to report the observance of adverse drug reactions [119]. Pharmacovigilance encompasses the totality of monitoring drug safety including identifying plausible adverse drug interactions, assessing risks and benefits as well as con- veying concerns over drug safety [120]. It is essential to regulate herbal medicine use as well as ensure appropriate quality control measures including quality specification; good manufacturing practices for herbal medicines, labeling and licensing schemes for manufacturing, imports and marketing should be enforced [121]. Also of importance is the need to extend knowledge on drug safety rather than the general approach of demonstrating toxicity. With an increased awareness and increasing number of the populace utilizing herbal medicines, more and more toxicological assessments need to be being conducted. This is expected to include an investigation into the potential for genotoxicity, reproductive toxicity, hepatotoxicity, nephrotoxicity and neurotoxicity of the phytomedicines [122, 123]. There are recommendations concerning the need to strengthen exper- tise in toxicology as well as determining newer approaches toward solving the present toxicological issues [124]. For example, the Caenorhabiditis elegans model has been pro- ven to be a reliable and invaluable tool in toxicological assessments, especially with respect to neurotoxic evalua- tions. In addition to its sharing a high sequence identity with several human genes as well as its anatomical and physio- logical characteristics, its genome has been fully sequenced and the nervous system has been extensively studied, thereby making it of immense benefit in toxicological assessments [125].

5 Conclusion

The use of herbal medicines is increasing, possibly because of their widespread promotion in the media as well as unsubstantiated health care claims. Although herbal medicines are beneficial, despite popular belief, they are not completely harmless, and HDIs may occur on con- comitant use with conventional drugs, but many possibly go unnoticed because of various factors. It is safer to view them as unrefined pharmaceuticals, capable of producing physiologic change, for better or worse.

Pharmacokinetic Herb-Drug Interactions

Most herbal medicines, unlike conventional drugs, comprise a complex mixture of chemical constituents. In order to better understand the detection and handling of HDIs, an expansion of knowledge on phytochemicals in herbal medicines is essential. Presently, in most cases, complete characterization of the bioactive compounds is not well defined, and information on toxicity and adverse effects are insufficient. It is expected that standardization, including chemical fingerprinting, would become potent tools for quality control of herbal medicines. However, because most of the available HDI information is based on individual case reports, animal studies and in vitro data, extensive research is required to confirm and assess the clinical significance of these potential interactions. HDIs may be underreported, and appropriate pharmacovigilance requires the collective responsibility of the patient, health practitioner and researchers. In this review, the pharmacokinetic (drug-metabolizing enzymes and drug transporter systems) mechanisms have been considered to play a role in these interactions. There are reports on the inductive role of PXR as a nuclear receptor; however, it is of importance to research other receptors, constitutive androstane receptor (CAR), and vitamin D-binding receptor (VDR), as these may also play an integral role in the mechanism of inductive processes involved in HDIs. Future perspectives for the application of HDIs are in new drug development and use of herbal medicines as adjuvants to conventional drugs. They may also be used for their additive or synergistic effect when coadministered with modern medicine. This may require a decreased dose of the conventional drug and possibly result in a reduction in the manifestation of side effects. In par- ticular, patients taking drugs with a narrow therapeutic index should be discouraged from using herbal products because of the ease of toxicity or ineffectiveness. In summary, HDIs certainly occur and may have serious consequences. However because they are under-re- searched, the present knowledge is incomplete. It is worth mentioning that further research and more controlled clinical studies are needed to clarify and determine the underlying mechanisms for these altered drug effects.

Compliance with Ethical Standards

Funding

No financial support was received for conducting this

study.

Conflict of interest

The authors report no competing interests.

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